Diabetes mellitus is one of the diseases that have recently seen the most dramatic increase in the number of patients in Japan and five to six million patients, including those undiagnosed, are estimated to exist. The number of patients with diabetes mellitus is almost comparable to those of patients with hyperlipidemia and hypertension. The cases of diabetes mellitus will certainly continue to increase in the years to come and may even double or triple sometime around 2010.
For the treatment of diabetes mellitus, two things are the most important, i.e., effective control of blood glucose levels and retarding the development and progression of complications such as retinopathy, neuropathy, nephropathy, peripheral circulation disorders and skin ulcerations.
The incidence of diabetic complications increases with time, or the number of years the patient has been suffering from diabetes mellitus. For example, under normal control of blood glucose, about one half of the patients with diabetes mellitus develop retinopathy in 10 years of affliction and in 20 years, almost all cases develop retinopathy, which is currently the leading cause of blindness (in each year, about 5000 people lose vision in retinopathy). Statistically, the incidence of neuropathy is substantially the same. About 20% of the patients with diabetes develop nephropathy in 10 years and about 30% of the patients starting renal dialysis have already suffered from diabetic nephropathy, which is one of the major reasons for the initiation of dialysis (in each year, about 6000 diabetic patients start renal dialysis). From now on, increasing number of cases that start renal dialysis will be estimated to be attributable to diabetic nephropathy. Peripheral circulation disorders occur in 10-40% of diabetic patients and they tend to worsen, which is one of the major reasons for amputations of the lower extremities.
In Japan, about one and a half million people are estimated to be suffering from diabetic complications. According to the Epidemiologic Study Report of the Japanese Ministry of Health and Welfare (1990), diabetic complications in Japan comprised 170,000 nephropathy cases, 600,000 retinopathy cases, 540,000 neuropathy cases and 230,000 cases of arteriosclerotic diseases. As of today, these numbers of the respective cases have certainly increased to higher levels.
Abnormal blood circulation in the retina of the eye has been pointed out as a cause of diabetic retinopathy. As a result of the measurement of circulation in the retina of patients at varying stages of retinopathy, it has been reported that the amount of circulation decreased with the progress of retinopathy. It has also been reported the distribution of blood vessels in the retina is abnormal. In short, poor circulation due to disorders in retinal small blood vessels causes chronic lack of oxygen and nutrients in the retinal tissue and this would induce pathological changes in diabetic retinopathy.
A predominant finding with diabetic neuropathy is the segmental demyelination of Schwann cells. The basement membrane thickening and occlusion of neurotrophic vessels have been recognized in patients with diabetic neuropathy. These vascular disorders would cause poor circulation in nerves, eventually inducing neuropathy.
Diabetic nephropathy is caused by disorders in renal glomerular vessels. Soon after the development of diabetes mellitus, the filtration rate of glomeruli is found to increase. After several years after the onset of the disease, basement membrane thickening and the growth of mesangium occur and, as a result, the vessel walls thicken and the bore of vessels becomes narrower, causing circulation disorder. These changes mostly occur in afferent glomerular arterioles and are seldom in efferent glomerular arterioles. Subsequently, these changes develop into glomerulosclerosis and, following the increase in blood pressure and the occurrence of proteinurea, further develop into nephropathy.
Diabetic peripheral circulation disorders are diseases that occur primarily in the peripheral vessels in the extremities to present with ischemic conditions by way of their constriction and occlusion. In most of these cases, occlusion occurs in more peripheral vessels and is prone to become serious, even advancing to a stage where amputation of the lower extremities is necessary.
Turning back to potassium channel activators, they are drugs that open potassium channels in cells, thereby relaxing the smooth muscle to display various actions. It is known that if applied to blood vessels, potassium channel activators increase the blood circulation by relaxing the vessels (see, for example, Japanese Patent Domestic Announcement No. 501010/1988). However, it has not been known at all that potassium channel activators are effective against diabetic complications such as retinopathy, neuropathy, nephropathy, peripheral circulation disorders and skin ulcerations.
It has been proved that the development and progression of diabetic complications can be checked to some extent by tight control of blood glucose levels. However, tight control of glucose levels can only be accomplished by intensive insulin therapy and it is not a practical method of treatment for patients with NIDDM (non-insulin-dependent diabetes mellitus) who account for the greater part of diabetic patients. Even if tight control of blood glucose is possible as in patients with IDDM (insulin-dependent diabetes mellitus), it can retard, but not prevent, the development of complications. In addition, tight control of blood glucose levels is hardly effective in curing complications or checking their progression if they are at an advanced stage. Given these limitations on the efforts to check the development and progression of complications solely by controlling blood glucose, a drug is desired that is capable of directly preventing the development and progression of diabetic complications. As of today, very few drugs meet this requirement and there is a very strong need to develop a truly effective drug which if used either alone or in combination with a hypoglycemic agent, can check the development and progression of diabetic complications.